Liposomal formulations for inhibiting SARS-CoV-2 replication and reducing lung inflammation

Abstract

In some aspects, provided herein are compositions of and methods for utilizing a sterically stabilized liposome carrier encapsulating a selected drug for the delivery of such drug effectual in the treatment of a mammal infected by a virus, such as SARS-COV-2, specifically in inhibiting the viral replication and reducing symptoms including lung inflammation. The compositions and methods disclosed herein provide a potential treatment for COVID-19 with improved patient compliance as they offer a less frequent dosing for the “long haulers” post COVID-19 initial infection.

What is claimed is: 
     
       1. A method of targeting delivery of an active agent to a point of viral attachment of a coronavirus to inhibit viral replication, the method comprising:
 administering a pharmaceutical composition in a subject in need thereof, wherein the pharmaceutical composition comprises the active agent encapsulated in a liposome carrier,
 wherein the liposome carrier comprises phosphatidylglycerol (PG), phosphatidylcholine (PC), and about 1% to about 5% polyethylene glycol distearoylphosphatidylethanolamine (PEG-DSPE), and 
 wherein the liposome carrier targets alveolar Type II pneumocytes and inhibits viral replication, 
 
 thereby targeting delivery of the active agent to the point of viral attachment to inhibit viral replication of the coronavirus. 
 
     
     
       2. The method of  claim 1 , wherein the coronavirus comprises SARS-CoV-2 or a variant thereof. 
     
     
       3. The method of  claim 1 , wherein the active agent comprises cromolyn sodium, albuterol sulfate, terbutaline, albuterol, ipratropium, pirbuterol, epinephrine, salmeterol, levalbuterol, formoterol, or a combination thereof. 
     
     
       4. The method of  claim 1 , wherein the active agent comprises a leukotriene inhibitor, and wherein the leukotriene inhibitor comprises montelukast, zafirlukast, zileuton, or an equivalent thereof. 
     
     
       5. The method of  claim 1 , wherein the active agent comprises Secretory Leukocyte Peptidase inhibitors, including SLPI, apol lipoprotein A-1 mimetics, including D-4F, monophosphoryl lipid A, or a combination thereof. 
     
     
       6. The method of  claim 1 , wherein the active agent comprises an antihistamine. 
     
     
       7. The method of  claim 1 , wherein the active agent comprises serine protease inhibitor. 
     
     
       8. The method of  claim 1 , wherein the active agent comprises an antibiotic, and wherein the antibiotic comprises amikacin, gentamicin, tobramycin, rifapentine, rifabutin, sparfloxacin, ciprofloxacin, quinolones, azithromycin, erythromycin, isoniazid, or a combination thereof. 
     
     
       9. The method of  claim 1 , wherein the active agent comprises a corticosteroid, and wherein the corticosteroid comprises budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, cortisone, betamethasone, or any combination or derivative thereof. 
     
     
       10. The method of  claim 1 , wherein the pharmaceutical composition comprises an aerosol formulation. 
     
     
       11. The method of  claim 10 , wherein the aerosol formulation has an effective life of at least two days and up to two weeks in the subject after the administering. 
     
     
       12. The method of  claim 11 , wherein the aerosol formulation has an effective life that is at least twice of an effective life of a corresponding formulation without the liposome carrier after administering to the subject. 
     
     
       13. The method of  claim 1 , wherein the administering comprises: (a) reducing levels of one or more of IL-6, IgE or eosinophils; (b) decreasing Eosinophil Peroxidase (EPO) activity in the bronchioalveolar lavage fluid (BAL) relative to levels prior to the administering; (c) reducing airway hyperresponsiveness (AHR) to Methacholine (Mch) relative to levels prior to the administering; or (d) any combination thereof. 
     
     
       14. The method of  claim 1 , wherein the administering comprises reducing lung inflammation, a marker of respiratory inflammation, or a combination thereof. 
     
     
       15. The method of  claim 1 , wherein the pharmaceutical composition is substantially devoid of cholesterol. 
     
     
       16. The method of  claim 1 , wherein the liposome carrier further comprises phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), or any combination or derivative thereof. 
     
     
       17. The method of  claim 1 , wherein the liposome carrier comprises a membrane portion, and wherein at least about 50%, about 60%, about 70% or about 75% of the active agent is displaced within the membrane portion of the liposome carrier at the time of the administration. 
     
     
       18. The method of  claim 1 , wherein the pharmaceutical composition contains about 1% to about 33% of the active agent. 
     
     
       19. The method of  claim 1 , wherein the pharmaceutical composition contains about 60% to about 99% PG, PC, PE, PS, PI, or a combination thereof. 
     
     
       20. The method of  claim 1 , wherein the pharmaceutical composition contains about 60% to about 99% synthetic palmitoyloleoyl-PG (POPG), polyoxyethylene (POE), synthetic palmitoyloleoyl-PC (POPC), or a combination thereof. 
     
     
       21. The method of  claim 1 , further comprising administering an additional pharmaceutical composition comprising the active agent or a second agent. 
     
     
       22. The method of  claim 21 , wherein the second agent comprises an agent suitable for treating an infection of the coronavirus. 
     
     
       23. The method of  claim 22 , wherein the second agent comprises an agent suitable for inhibiting viral replication of the coronavirus. 
     
     
       24. The method of  claim 22 , wherein the second agent is administered before, after, or concurrently with administration of the pharmaceutical composition comprising the active agent encapsulated in the liposome carrier. 
     
     
       25. The method of  claim 22 , wherein the second agent is a monoclonal antibody, a protease inhibitor, an RNA-dependent RNA polymerase inhibitor, or any combination thereof. 
     
     
       26. The method of  claim 25 , wherein the monoclonal antibody comprises bamlanivimab, etesevimab, casirivimab, imdevimab, sotrovimab, or a combination thereof. 
     
     
       27. The method of  claim 25 , wherein the protease inhibitor comprises nirmatrelvir, ritonavir, or a combination thereof. 
     
     
       28. The method of  claim 25 , wherein the RNA-dependent RNA polymerase inhibitor, is an active metabolite of remdesivir.